Discovery of Coumarin-Based MEK1/2 PROTAC Effective in Human Cancer Cells

The Raf/MEK/ERK pathway is a crucial signal path which is closely associated with the proliferation, differentiation, and Apoptosis of tumors. MEK1/2 is a key kinase target in the pathway, with ERK1/2 acting as the main substrate of it. Despite the rapid development of MEK1/2 inhibitors, acquired resistance still happens and remains a significant problem. Most of the inhibitors possess a similar diarylamine scaffold. Here we designed and synthesized a series of MEK1/2 degraders based on a coumarin derivative which was a potent non-diarylamine allosteric MEK1/2 inhibitor. P6b among them showed the most potent degradation effect, with DC₅₀ values of 0.3 μM and 0.2 μM in MEK1 and MEK2 degradation, respectively. An antiproliferation assay showed that it more significantly inhibits the growth of A375 cells (IC₅₀= 2.8 μM) compared to A549 cells (IC₅₀ = 27.3 μM). To sum up, we discovered P6b with a non-diarylamine scaffold for the first time as a potent MEK PROTAC effective in human Cancer cells.